U.S. patent application number 10/978896 was filed with the patent office on 2006-05-04 for rs 1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol, process for preparation thereof and process for preparation of rs betaxolol.
Invention is credited to Sanjay Pandurang Borikar, Dinesh Ramesh Garud, Mukund Keshav Gurjar, Ramesh Anna Joshi, Muthukrishnan Murugan.
Application Number | 20060094903 10/978896 |
Document ID | / |
Family ID | 36262958 |
Filed Date | 2006-05-04 |
United States Patent
Application |
20060094903 |
Kind Code |
A1 |
Joshi; Ramesh Anna ; et
al. |
May 4, 2006 |
RS 1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol,
process for preparation thereof and process for preparation of RS
betaxolol
Abstract
The present invention relates to RS
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
the formula (1), process for preparation thereof by selective
allylation of p-hydroxy phenyl ethanol and use thereof in a
preparation of RS betaxolol of formula (2) ##STR1##
Inventors: |
Joshi; Ramesh Anna; (Pune,
IN) ; Murugan; Muthukrishnan; (Pune, IN) ;
Garud; Dinesh Ramesh; (Pune, IN) ; Borikar; Sanjay
Pandurang; (Pune, IN) ; Gurjar; Mukund Keshav;
(Pune, IN) |
Correspondence
Address: |
MORGAN & FINNEGAN, L.L.P.
3 World Financial Center
New York
NY
10281-2101
US
|
Family ID: |
36262958 |
Appl. No.: |
10/978896 |
Filed: |
November 1, 2004 |
Current U.S.
Class: |
564/348 |
Current CPC
Class: |
C07C 217/34
20130101 |
Class at
Publication: |
564/348 |
International
Class: |
C07C 213/08 20060101
C07C213/08 |
Claims
1. RS 1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino
propan-2-ol of the formula 1 ##STR12## or an acid salt thereof
2. A process for the preparation of RS
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
the formula 1 or an acid salt thereof ##STR13## which comprises:
(a) selectively allylating 2-(4-hydroxyphenyl)-ethanol of formula 3
with a base and an organic solvent to give
4-(2-allyloxy-ethyl)-phenol of formula 4; ##STR14## (b)
O-Alkylating 4-(2-allyloxy-ethyl)-phenol of formula 4 by treating
with epichlorohydrin in the presence of an alkali to obtain a
mixture of compounds of formulae 5 and 6 ##STR15## (c) treating the
mixture of compounds of formulae 5 and 6 with isopropyl amine to
give 1-[4-(2-allyloxy-ethyl-phenoxy)-3-isopropylamino-propan-2-ol
of the formula 1; (d) and if desired, converting compound of
formula 1 into an acid salt thereof by treating it with a
corresponding acid.
3. A process as claimed in claim 2 wherein the base used in step
(a) is selected from the group consisting of sodium hydride or
potassium t-butoxide.
4. A process as claimed in claim 2 wherein the solvent used in step
(a) is an ethereal solvent comprising of tetrahydrofuran or a polar
solvent selected from the group consisting of DMSO and DMF.
5. A process as claimed in claim 2 wherein the alkali used in step
(b) is an alkali hydroxide selected from the group consisting of
sodium hydroxide and potassium hydroxide.
6. A process as claimed in claim 2 wherein the compound of formula
1 is treated with hydrochloric acid to obtain a hydrochloride of
formula 8 ##STR16##
7. A process as claimed in claim 2 wherein the compound of formula
1 is treated with maleic acid to give maleate of formula 7
##STR17##
8. A process as claimed in claim 6 wherein the conversion of the
compound of formula 1 to its hydrochloride salt of formula 8 is
carried out in the presence of a solvent selected from a
hydrocarbon selected in turn from the group consisting of toluene
and cyclohexane, ethers selected in turn from the group consisting
of diethyl ether and diisopropyl ether; alcohols selected in turn
from the group consisting of ethanol, methanol and isopropanol.
9. A process as claimed in claim 7 wherein the conversion of the
compound of formula 1 to its maleate salt of formula 7 is carried
out in the presence of an ethereal solvent selected from the group
consisting of diisopropyl ether and diethyl ether.
10. A process for the preparation of a betaxolol of formula 2 from
RS 1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol
of the formula 1 ##STR18## comprising cyclopropanating compound of
formula 1 to obtain the racemic betaxolol of formula 2.
11. A process as claimed in claim 10 wherein the cyclopropanation
of compound of formula 1 is carried out with diiodomethane in
presence of Zn--Cu couple (Simmons Smith Reaction) or diethyl zinc
in hexane (Furukawa modification).
Description
FIELD IF THE INVENTION
[0001] The present invention relates to RS
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
the formula (1), process for preparation thereof and use thereof in
a preparation of RS betaxolol of formula (2) More particularly the
present invention relates to the preparation of RS
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol by
selective allylation of p-hydroxy phenyl ethanol. ##STR2##
BACKGROUND OF THE INVENTION
[0002] Racemic betaxolol of formula (2) is a .beta.-adrenoreceptor
antagonist with a pharmacological and pharmacokinetic profile for
the treatment of chronic cardiovascular diseases like glaucoma. The
disease glaucoma is characterized by progressive damage to the
optic nerve caused by the increased pressure within the eye.
Glaucoma is a serious disease of the eye, which may lead to the
loss of peripheral vision and if untreated total blindness.
[0003] .beta.-adrenoreceptor antagonist (.beta.-blockers) are
popularly used to lower intraoccular tension, other conditions of
increased intraoccular pressure and management of essential
hypertension. The principle effect of .beta.-adrenoreceptor blocker
is to reduce cardiac activity by diminishing or preventing
.beta.-adrenoreceptor stimulation i.e. by reducing the rate and
force of contraction of the heart.
[0004] The processes employed for the preparation of betaxolol in
the art involve protecting the phenol functional group so that the
alcohol functionality can be alkylated. The resulting protection
and deprotection steps extend the length of synthesis.
[0005] Manoury et al., (U.S. Pat. No. 4,252,984) describes the
preparation of betaxolol which involves the benzylation of the
phenolic alcohol of 4-hydroxyphenethanoic acid. The ester group is
then reduced to alcohol and then condensation of
2-(4-benzyloxyphenyl)ethanol with cyclopropyl methyl halide to
yield cyclopropyl methyl2-(4-benzyloxyphenyl)ether. It is then
debenzylated and treated with epichlorohydrin to yield the
compound, which on treatment with isopropylamine gives the
betaxolol.
[0006] In another U.S. Pat. No.4,760,182 by Ippolito et al.,
4-hydroxyphenethanol is converted to a phenoxide anion with a base
and then reacting it with epichlorohydrin to yield
1-(4-(2-hydroxyethyl)phenoxy)2,3-epoxypropane.
[0007] Wang et al., (U.S. Pat. No. 5,731,463 ) describes selective
alkylation of the 4-hydroxy phenethanol via an oxygen dianion to
produce intermediate which on reaction with epichlorohydrin and
subsequent addition of isopropylamine produces the end product
betaxolol.
[0008] In all the above processes cyclopropylmethyl halide has been
employed for introducing cyclopropyl group as a reactive
intermediate. The cyclopropylmethyl halide, is expensive, highly
lachrymetric and unstable. These limitations make the reported
processes economically unviable and difficult to scale up.
[0009] Therefore it is necessary to develop a short, simple, an
economically viable alternative process for RS betaxolol wherein
the use of cyclopropylmethyl halide is avoided, and steps involving
protection and deprotection are avoided.
OBJECTS OF INVENTION
[0010] The object of present invention therefore is to provide a
process for preparation of RS betaxolol. Another object is to avoid
use of highly lachrymetric and unstable cyclopropylmethyl halide
and also to avoid lengthier steps involving protection and
deprotection of phenolic hydroxy group.
SUMMARY OF THE INVENTION
[0011] The above objects are fulfilled by providing a novel RS
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol
compound of formula (1), process for preparation thereof and use
thereof in preparation of RS betaxolol of formula (2).
[0012] Accordingly, the present invention firstly provides RS
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
the formula 1 ##STR3## or an acid salt thereof
[0013] The present invention also provides a process for the
preparation of RS
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
the formula 1 or an acid salt thereof ##STR4## which comprises:
[0014] a) selectively allylating 2-(4-hydroxyphenyl)-ethanol of
formula 3 with a base and an organic solvent to give
4-(2-allyloxy-ethyl)-phenol of formula 4; ##STR5## [0015] b)
O-Alkylating 4-(2-allyloxy-ethyl)-phenol of formula 4 by treating
with epichlorohydrin in the presence of an alkali to obtain a
mixture of compounds of formulae 5 and 6 ##STR6## [0016] c)
treating the mixture of compounds of formulae 5 and 6 with
isopropyl amine to give
1-[4-(2-allyloxy-ethyl-phenoxy)-3-isopropylamino-propan-2-ol of the
formula 1; [0017] d) and if desired, converting compound of formula
1 into an acid salt thereof by treating it with a corresponding
acid.
[0018] In one of embodiment of the invention, the base used in step
(a) is selected from the group consisting of sodium hydride or
potassium t-butoxide.
[0019] In another embodiment of the invention, the solvent used in
step (a) is an ethereal solvent comprising of tetrahydrofuran or a
polar solvent selected from the group consisting of DMSO and
DMF.
[0020] In still another embodiment of the invention, the alkali
used in step (b) is an alkali hydroxide selected from the group
consisting of sodium hydroxide and potassium hydroxide.
[0021] In another embodiment of the invention, the compound of
formula 1 is treated with hydrochloric acid to obtain a
hydrochloride of formula 8 ##STR7##
[0022] In another embodiment of the invention, the compound of
formula 1 is treated with maleic acid to give maleate of formula 7
##STR8##
[0023] In another embodiment of the invention, the conversion of
the compound of formula 1 to its hydrochloride salt of formula 8 is
carried out in the presence of a solvent selected from a
hydrocarbon selected in turn from the group consisting of toluene
and cyclohexane, ethers selected in turn from the group consisting
of diethyl ether and diisopropyl ether; alcohols selected in turn
from the group consisting of ethanol, methanol and isopropanol.
[0024] In another embodiment of the invention, the conversion of
the compound of formula 1 to its maleate salt of formula 7 is
carried out in the presence of an ethereal solvent selected from
the group consisting of diisopropyl ether and diethyl ether.
[0025] The present invention also provides a process for the
preparation of a betaxolol of formula 2 from RS
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
the formula 1 ##STR9## comprising cyclopropanating compound of
formula 1 to obtain the racemic betaxolol of formula 2.
[0026] In another embodiment cyclopropanation of compound of
formula 1 is carried out with diiodomethane in presence of Zn--Cu
couple (Simmons Smith Reaction) or diethyl zinc in hexane (Furukawa
modification).
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention provided RS
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
the formula (1), process for preparation thereof and use thereof in
preparation of RS betaxolol of formula (2). ##STR10##
[0028] The general process involved in the preparation of compound
of formula 1 and its subsequent conversion to compound of formula 2
is given in the reaction scheme on the following page. The process
of the invention broadly comprises [0029] (a) selectively
allylating 2-(4-hydroxyphenyl)-ethanol of formula (3) with a base
and an organic solvent to give 4-(2-allyloxy-ethyl)-phenol of
formula (4); [0030] (b) O-Alkylating 4-(2-allyloxy-ethyl)-phenol of
formula (4) by treating with epichlorohydrin in the presence of an
alkali to obtain the mixture of compounds of the formulae (5 and
6). Treating the mixture of compounds of the formulae (5 and 6)
with isopropyl amine to give
1-[4-(2-allyloxy-ethyl-phenoxy)-3-isopropylamino-propan-2-ol of the
formula (1). [0031] (c) Treating
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
the formula (1) with hydrochloric acid in IPA to give hydrochloride
of formula (8). [0032] (d) Treating
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
the formula (1) with maleic acid in ether to give maleate of
formula (7).
[0033] The compound of formula 1 is then cyclopropanated by
conventional methods such as Simmon-Smith reaction or Furukawa
modification to obtain racemic betaxolol of formula 2.
[0034] The base used in step (a) can be sodium hydride or potassium
t-butoxide and the solvent used in step (a) can be an ethereal
solvent such as tetrahydrofuran or a polar solvent such as DMSO,
DMF. In step (b) the alkali used is an alkali hydroxide such as
sodium hydroxide or potassium hydroxide.
[0035] The solvent used for the preparation of hydrochloride salt
of compound of formula 1 is either a hydrocarbon such as toluene or
cyclohexane; ether such as diethyl ether or diisopropyl ether; or
an alcohol such as ethanol, methanol or isopropanol. The solvent
used for preparing the maleate salt of compound of formula 1 is an
etheral solvent such as diisopropyl ether or diethyl ether.
##STR11##
[0036] The cyclopropanation in step (c) may be carried out with
diiodomethane in presence of Zn--Cu couple (Simmons Smith) or
diethyl zinc in hexane. (Furukawa modification) to obtain RS
betaxolol of formula (2).
[0037] The process of the present invention is described herein
below with reference to the following examples, which are
illustrative and should not be construed to limit the scope of the
present invention in any manner.
EXAMPLE-1
This Example Describes the Preparation of
4-[(2-Allyloxy)-ethyl)]-phenol of Formula (4)
[0038] A reaction flask was charged with 4-hydroxy phenethyl
alcohol of formula (3) (5 g, 0.036 mol), potassium t-butoxide
(12.17 g, 0.10 mol) and 20 ml of DMSO. The mixture was stirred
under nitrogen at 50.degree. C. for 30 minutes. A solution of allyl
chloride (3.00 ml, 0.036 mol) was added dropwise to the reaction
mixture at room temperature and further stirred for 50 min. The
reaction mixture was subsequently quenched with 40 ml of water. The
aqueous mixture was washed three times with 10 ml portions of
toluene to remove impurities. The product was extracted from
neutralized aqueous mixture with toluene. The toluene extract was
then washed with water and concentrated under vacuum to afford the
compound of formula (4) as oil (3.07 g, 48%). The characterization
of the product was done by .sup.1H NMR and the results are
mentioned hereinbelow.
[0039] .sup.1H NMR: 2.87 (t, 2 H, CH.sub.2--C); 3.64 (t, 2 H,
CH.sub.2--O); 4.02 (d, 2 H, CH.sub.2--CH.dbd.CH.sub.2 5.20, 5.30
(dd, 2 H, olefinic); 5.94 (m, 1 H, olefinic); 6.74, 7.07
(A.sub.2B.sub.2, 4 H, aromatic)
EXAMPLE-2
This Example Describes the Preparation of
2-[4-(2-allyloxy-ethyl)-phenoxymethyl]-oxirane of Formula (5)
[0040] To the solution of aromatic phenol of formula (4) (2.83 g,
0.016 mol) in a mixture of acetone: water (4:1) was added
sequentially NaOH (0.63 g, 0.016 mol), epichlorohydrin (6.21 g,
0.079 mol) and the reaction mixture was stirred under reflux for 2
hours, the mixture was concentrated and the residue partitioned
between ethyl acetate and water. The organic layer was dried over
anhydrous sodium sulphate, filtered and concentrated. The crude
product was purified by silica gel chromatography using ethyl
acetate and pet ether (1:9) as an eluent to afford compound of
formula (5) (2.79 g 75%) as oil.
[0041] .sup.1H NMR: 2.7-2.9 (m, 4 H, CH.sub.2--C, CH.sub.2--O);
3.64 (t, 2 H, CH.sub.2--O); 3.75 ( m, 1 H, CH.sub.2--O); 4.02 (m, 3
H, CH.sub.2--CH.dbd.CH.sub.2, CH.sub.2--O); 4.16 (dd, 1 H, CH--O);
5.20, 5.30 (dd, 2 H, olefinic); 5.94 (m, 1 H, olefinic); 6.84, 7.14
(A.sub.2B.sub.2, 4 H, aromatic).
EXAMPLE-3
This Example Describes the Preparation of
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
Formula (1)
[0042] A solution of the compound of formula (5) (3.70 g, 0.016
mol), isopropyl amine (7.46 ml, 0.127 mol) in methanol (20 ml) was
stirred under reflux for 2 hours and then concentrated. The residue
was partitioned between chloroform and water. The organic layer was
dried over anhydrous sodium sulphate, filtered and concentrated.
The residue was crystallized from pet ether to afford compound of
formula (1) as a white solid 3.47 g (75%) mp 52-53.degree. C.
[0043] .sup.1H NMR: 1.08, 1.09 (2 S, 6 H, (CH.sub.3).sub.2N); 2.69
(m, 1 H, CH--CH.sub.3); 2.73-2.93 (m, 7 H, CH.sub.2--C,
CH.sub.2--O, N--H, O--H, N--CH); 3.61 (t, 2 H, O--CH.sub.2);
3.92-4.00 (m, 4 H, CH.sub.2--O); 4.07 (m, 1 H, CH--OH); 5.20, 5.30
(dd, 2 H, olefinic); 5.94 (m, 1 H, olefinic); 6.85, 7.16
(A.sub.2B.sub.2, 4 H, aromatic).
Mass: M.sup.+=293.
EXAMPLE-4
This Example Describes the Preparation of maleate salt of
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
Formula (7)
[0044] Compound of formula (1) (4 g, 0.014 mol) was dissolved in
ether (25 ml) to this maleic acid (1.43 g, 0.012 mol) was added and
stirred for 1 hr. Filtered the white solid, which was maleate salt
of formula (7) (4.75 g, 85%) mp 71.degree. C.
EXAMPLE-5
This Example Describes the Preparation of hydrochloride salt of
1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of
Formula (8)
[0045] To a solution of compound of formula (1) (2.50 g) in 15 ml
of toluene, isopropanol-HCl (1 eq) (5 ml) was added drop wise under
nitrogen atmosphere with stirring (untill pH=2). The reaction
mixture was stirred for 1 h, concentrated and again 5 ml of toluene
was added, stirring continued for 15 min. This process was repeated
twice, finally solvent was removed completely and diethyl ether was
added to precipitate the solid. Filtered under nitrogen atmosphere
and dried to obtain the compound of formula (8) 2.42 g (86%) mp
101-104.degree. C.
EXAMPLE-6
[0046] This Example Describes the Preparation of Betaxolol of
Formula (2)
[0047] To a stirred solution of compound of formula (1) (1 g, 0.003
mol) in dry toluene (5 ml), diethylzinc (1.1 M solution in toluene,
14 ml, 0.017 mol) was added at 0.degree. C. under nitrogen
atmosphere followed by diiodomethane (1.38 ml, 0.017 mol). The
reaction was stirred for 16 h at 0.degree. C. and poured over cold
aqueous solution of ammonium chloride. The organic layer was
separated and the aqueous layer extracted repeatedly with toluene.
The combined organic layer was washed with a solution of sodium
thiosulphate, dried over anhydrous sodium sulphate, filtered and
concentrated to yield racemic betaxolol of formula (2) 1.6 g (84 %)
mp 70-72.degree. C. as a white solid.
M.sup.+=307.
[0048] .sup.1H NMR: 0.20 (q, 2 H, cyp); 0.53 (q, 2 H, cyp); 1.07
(m, 1 H, cyp); 1.08, 1.09 (2 S, 6 H, (CH3).sub.2N); 2.69 (m, 1 H,
CH--CH.sub.3); 2.85 (m, 4 H, CH.sub.2--C, CH.sub.2--O); 3.27 (d, 2
H, O--CH.sub.2); 3.61 (t, 3 H, CH--O); 3.95 (d, 2 H, CH.sub.2--O);
4 (m, 1 H, CH--OH); 6.85, 7.16 (A.sub.2B.sub.2, 4 H, aromatic).
* * * * *